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Leveraging non-canonical role of CDK9 to Target CCNE1-amplified high-grade serous ovarian cancer

Award Number: K99CA315379
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/21/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Leveraging non-canonical role of CDK9 to Target CCNE1-amplified high-grade serous ovarian cancer - Project Summary/abstract Genomic instability, a common feature of many cancer types, can be leveraged to develop targeted treatments to significantly improve cancer treatment effectiveness. Thus, the characterization of such processes is essential for identifying novel tumor-specific therapeutic vulnerabilities. This research proposal centers on the characterization and exploration of non-canonical functions of Cyclin-dependent kinase 9 (CDK9) in the context of genomic integrity maintenance and treatment of high-grade serous ovarian cancer (HGSOC), a particularly aggressive cancer type known for its poor prognosis and limited treatment options. HGSOC is often marked by the amplification of the CCNE1 gene, which is associated with high-lethality rates and resistance to therapies. My preliminary studies highlight four critical mechanisms that offer an alternative perspective on targeting CDK9 for cancer therapy: 1) The existence of a transcription-independent role for CDK9 in the DNA double-strand break (DSB) repair by homologous recombination (HR). 2) CDK9 inhibition phenocopies BRCA1 loss, impacting HR signaling. 3) CDK9 phosphorylates the chromatin remodeler CHD1, critical for HR repair. 4) Acute CDK9 depletion triggers replication stress and apoptosis. Suggesting that CDK9 might be a targetable vulnerability in tumors that combine oncogenic-induced replication stress and vulnerability to HR deficiency. Given that CCNE1- amplified HGSOC present high levels of replication stress and mutual exclusivity with BRCA1 loss, due to synthetic lethality, I hypothesize that CDK9 inhibition represents a targetable vulnerability of CCNE1-amplified HGSOC. During the K99 phase of this award, I will define how CDK9 regulates chromatin remodeling and DNA repair and evaluate the therapeutic potential of targeting CDK9 in CCNE1-amplified HGSOC cells. During the R00 phase, I will identify mechanisms of resistance to CDK9 inhibition and determine how CDK9 function during DNA replication, preventing replication stress. These studies will reveal potential biomarkers and combination strategies to improve CDK9-targeted therapies. This project will dissect how CDK9 maintains genomic integrity and translate this knowledge into a framework for using CDK9i to treat CCNE1-amplified HGSOC tumors in clinical settings. In addition to my scientific goals, I have also designed a comprehensive training plan that will prepare me for the transition to independence. This includes: 1) guidance from my mentor, Dr. Alvaro Monteiro, and three renowned advisory committee members, Drs. Derek Duckett, Douglas Cress and Florian Karreth; 2) development of new skills in preclinical models for ovarian cancer, by collaborating with the Physician Scientist, Dr. Erin George; 3) theoretical and hands-on training on cutting-edge technology to study DNA replication, in collaboration with Dr. Huzefa Dungrawala, an the expert in the field; 4) as well as mastering the professional skills needed to guide my transition to independence and my success as an independent principal investigator.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $109,107 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	1	7/21/2026	NEW	$109,107
														Subtotal = $109,107

Grand Total All Awards = $109,107

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Leveraging non-canonical role of CDK9 to Target CCNE1-amplified high-grade serous ovarian cancer

Award Number: K99CA315379

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/21/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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